This describes the use of Romiplostim other than its standard uses, as in ITP and aplastic anemia.

1. Management of
other thrombocytopenia
with Romiplostim
Dr. Pritish Chandra Patra
Associate Professor
Dept. of Clinical Hematology
IMS & SUM Hospital, Bhubaneswar

2. A normal platelet count
• A study from the USA involving over 12,000 adults in the National Health and Nutrition
Examination Survey (NHANES) database found the following:
• Platelet count
• Range from: 150,000 - 450,000/microL
• Slightly higher mean values in females (266,000/microL) than males (237,000/microL)
• Slightly higher in younger people than older people

3. What is a low platelet count?
• Thrombocytopenia- defined as a platelet count below the lower limit of normal: <150,000/microL
• Degrees of thrombocytopenia- further subdivided into
• Mild (100,000 - 150,000/microL)
• Moderate (50,000 - 99,000/microL)
• Severe (<50,000/microL)
• Numbers Vs underlying disease (eg, in ITP, platelet count <30,000/microL - severe thrombocytopenia)
• Clinical significance- Severe thrombocytopenia (platelet count <30,000 - 50,000/microL)
• greater risk of bleeding- intracranial
• implies a greater likelihood for needing treatment

4. Thrombocytopenia:
basic
mechanisms
Decreased platelet production (IBMFS, AA, Leukemia, CIT)
Ineffective platelet production (MDS, Megaloblastic anemia)
Increased platelet destruction (ITP, HLH)
Increased platelet consumption (MAHA- DIC, TTP, HUS)
Platelet sequestration (Hypersplenism)
Combination of multiple above mechanisms

5. Thrombopoietin (TPO)
• Produced in
• Liver- parenchymal cells & sinusoidal endothelial cells
• Kidney- proximal convoluted tubule cells
• Striated muscle
• Bone marrow stromal cells
• TPO is bound to the surface of platelets and
megakaryocytes by the MPL receptor.
• TPO regulates the differentiation
of megakaryocytes and platelets.
• Inside the platelets it gets destroyed, while inside the
megakaryocytes it gives the signal of their maturation
and consecutively more platelet production.
Kaushansky K (May 2006). "Lineage-specific hematopoietic growth factors". The New England Journal of Medicine. 354 (19): 2034–45.
Bussel JB et al. A Review of Romiplostim Mechanism of Action and Clinical Applicability. Drug Des Devel Ther. 2021 May 26;15:2243-2268.

6. Generations of TPO-RA
David J. Kuter. New Thrombopoietic Growth Factors. Clinical Lymphoma & Myeloma, Vol. 9, Suppl. 3, S347-S356, 2009

7. TPO-RA: Romiplostim Vs Eltrombopag
• Romiplostim:
• A peptibody comprising four TPO-R binding domains with high
affinity for the TPO-R (MPL) and one carrier Fc domain.
• Binds to and activates the TPO-R on megakaryocyte precursors in
bone marrow.
• Binds in the same manner as endogenous TPO and can displace
TPO from its receptor.
• Romiplostim activates many of the same pathways as TPO,
leading to sustained improvement of platelet counts with
continued treatment.
• Different TPO-RAs activate the TPO-R in different ways
• Romiplostim activates the extracellular domain of the TPO-R
• Eltrombopag activates the transmembrane portion of the TPO-R

8. TPO-RA: Romiplostim Vs Eltrombopag

9. Approved indications
• Eltrombopag: by US FDA & EMA
• Chronic-ITP
• Hep-C associated TCP
• SAA
• Romiplostim:
• ITP
• HS-ARS
• although not approved for use in aplastic anemia by US FDA &
EMA, it similarly stimulates the proliferation of residual stem and
progenitor cells in patients with aplastic anemia (approval has
been received for refractory aplastic anemia in Japan and Korea).

10. Other indications

11. Chemotherapy Induced Thrombocytopenia (CIT)
(p < .001)

12. • 64% (n = 28) resumed the same chemotherapy regimen that had led to CIT
• 36% (n = 16) resumed a different chemotherapy regimen
• 58% (11/19) resumed full-dose or increased dose chemotherapy who had reduction in chemotherapy dose before
enrollment
• Only 6.8% (n = 3) experienced chemotherapy dose reduction or dose delay as a result of recurrent CIT within the
specified time period
• 64% (28/44) patients who resumed chemotherapy continued taking romiplostim for more than 6 months, and
• 27% (12/44) continued for more than 1 year.
• The longest exposure to romiplostim was 34 months.
Soff GA et al. J Clin Oncol. 2019 Nov 1;37(31):2892-2898.
Secondary end points:

16. • Dose:
• Beginning at 2-4 mcg/kg, increased by 1-2 mcg/kg per week  to target platelet count 100,000-150,000/mcL
• Maximum dose: 10 mcg/kg weekly
• TPO-RAs for CIT may increase the risk of venous thromboembolism (VTE) in patients with cancer.
Therefore, caution is warranted.
Chemotherapy Induced Thrombocytopenia (CIT)

18. Hematopoietic Syndrome of Acute Radiation Syndrome (HS-ARS)
• Romiplostim- reduces lethality and pancytopenia by multiple mechanisms
• stimulation of splenic progenitor cells
• induction of pulmonary megakaryocytopoiesis
• prevention of bone marrow cell death
• modulation of DNA repair
• production of cytokines
• Romiplostim has also been examined in combination with g-CSF and rEPO in irradiated mice,
which led to 100% survival at day 30.
• Recommended dose: 10 mcg/kg administered once as a subcutaneous injection. Administer the
dose as soon as possible after suspected or confirmed exposure to radiation levels greater than 2
gray (Gy).
Bussel JB et al. A Review of Romiplostim Mechanism of Action and Clinical Applicability. Drug Des Devel Ther. 2021 May 26;15:2243-2268.

19. Chronic liver disease
• CLD, especially cirrhosis- often have thrombocytopenia
• In advanced CLD
• TPO declines as a result of splenomegaly and hepatic damage such that the liver cannot make even
normal amounts of TPO.
• accelerated platelet destruction and reduced platelet production
• Avatrombopag and lusutrombopag, have been approved specifically to increase the platelet
count in patients with thrombocytopenia and liver disease undergoing a procedure.
• Eltrombopag is approved to treat thrombocytopenia in patients with hepatitis C with liver
disease to allow for the initiation and maintenance of interferon-based therapy.
• Romiplostim case reports have shown to improve platelet counts in a patient with
• hepatocellular carcinoma
• hepatitis C

20. Peri-surgical
• Romiplostim has been used successfully to increase platelet counts in patients with
thrombocytopenia caused by different underlying pathologic conditions in association with
various surgical procedures.
• The underlying causes of thrombocytopenia included ITP, chronic liver disease, hematologic
malignancy, and drug-related and hereditary causes.
• Retrospective data indicate that romiplostim can also improve platelet counts to levels conducive
for performing various surgeries, including major cardiac, orthopedic, gastrointestinal, and
neurologic surgeries.
• Romiplostim >>> Eltrombopag

22. ROMIPLOSTIM

23. Romiplostim reverts the thrombocytopenia in
Dengue Hemorrhagic Fever
Margarita S. Rodriguez-Mejorada et al; Refractory Thrombocytopenia Associated with Dengue Hemorrhagic Fever Responds to Romiplostim. Blood 2010; 116 (21): 4668.

24. ROMIPLOSTIM

25. Common causes of
thrombocytopenia in
ICU patients:
• Sepsis
• Disseminated intravascular coagulation
• Consumption (eg, major trauma, cardiopulmonary bypass)
• Dilution (with massive transfusion)
• Myelosuppressive chemotherapy
• Mechanical circulatory support devices (eg, intra-aortic balloon pump)
Less common but
important causes of
thrombocytopenia that
should not be missed:
• Heparin-induced thrombocytopenia
• Hemophagocytic syndrome
Uncommon causes of
thrombocytopenia that
develop during ICU
admission:
• Drug-induced thrombocytopenia (other than heparin or cytotoxic
chemotherapy)
• Leukemia, myelodysplasia, aplastic anemia, etc, unless abnormalities
were already present before ICU admission
• Thrombotic thrombocytopenic purpura
• Immune/idiopathic thrombocytopenia
• Post-transfusion purpura
Causes of thrombocytopenia in the ICU
Zarychanski R, et al. ASH Education Program Book. 2017 Dec 8;2017(1):660-6.

26. • Firstly, it was assumed that the only mechanism of
thrombocytopenia in sepsis was the decreased
production of platelets
• Lately it was found in studies that
• Reticulated platelet percentage (RP%) and thrombopoietin
(TPO); both markers were increased in septic patients.
• Significant endotoxemia in sepsis increases pro-inflammatory
markers such as TNF-α, IL-1, IL-6, and IL-8, which are known for
being thrombopoietic, meaning that it can increase platelet
production
• Thus in patients with sepsis the thrombopoiesis rate is high,
but the platelet consumption surpasses platelet production
Proposed mechanism of thrombocytopenia in sepsis
Gonzalez DA, et al. Cureus. 2022 May 27;14(5).

27. Time course of thrombocytopenia in septic shock
• Septic shock:
• In patients with septic shock who
develop thrombocytopenia, despite
signs of clinical improvement, on
average, platelet recovery is not
anticipated until several days after
vasopressor independence.
• The median time from
discontinuation of vasopressors to
recovery of platelet counts above 100
x 109/L is 2 days (IQR, 0-4)
• Mean platelet count in patients with septic shock who developed
thrombocytopenia after ICU admission.
• Time axis is anchored to the day that vasopressors were
discontinued (day 0). Only data for survivors are included
Menard CE, et al. Intensive Care Med Exp. 2016; 4(Suppl 1):A586

29. Practical issues
• Route of administration needs to be considered when choosing a TPO-RA.
• More frequent hospital visits are required until platelet counts are stabilized.
• Eltrombopag needs to be taken on an empty stomach (≥2 hours before or 4 hours after calcium-
rich foods) and may not be suitable in patients with absorption problems, nausea, transaminitis,
or irregular mealtimes.
• Discontinuation of romiplostim should be done in a stepwise fashion, as abruptly stopping
treatment can lead to rebound thrombocytopenia in patients who responded to treatment.
• Platelet counts should be monitored at least weekly and for ≥2 weeks after discontinuation.
• The dose of romiplostim should be increased 1 μg/kg/week if platelet counts decrease to <50 ×
109/L or the patient exhibits symptoms.

30. Summary
• Thrombopoietin is involved in multiple steps of platelet production, from the stem cell through development of mature
megakaryocytes and possibly even platelet release.
• Romiplostim, an TPO-RA acts by increasing platelet production and therefore increases platelet counts.
• Increased platelet counts can reduce the need for platelet transfusions and decrease bleeding events in multiple
conditions.
• Romiplostim binds to and activates the TPO-R on megakaryocyte precursors, activating multiple cell-signaling pathways,
leading to enhanced cell growth and cell viability, which results in increased platelet production.
• Studies have also shown romiplostim to be effective in improving platelet counts in various preclinical and clinical settings,
including CIT, aplastic anemia, animal models of acute radiation syndrome, and liver disease.
• Although many indications have not been approved yet, these studies highlight the versatility of romiplostim in
thrombocytopenic conditions other than ITP. In particular, in severe aplastic anemia, for which eltrombopag has been
licensed as upfront treatment in combination with standard immunosuppressive therapy, a recent study showed similar
efficacy of romiplostim.

31. Use of TPO Receptor Agonists
• Immune thrombocytopenia (ITP)
• Aplastic anemia
• Hepatitis C related thrombocytopenia
• Liver disease
• Chemotherapy-induced
thrombocytopenia (CIT)
• Radiation protection (HS-ARS)
• Pre-procedure thrombocytopenia
• Inherited thrombocytopenia (MYH-9)
• Stem cell transplant
• AML induction/remission chemotherapy
• Drug-induced thrombocytopenia
• Myelodysplastic syndromes (MDS)

32. Thank You

33. MOA of TPO-RA: Romilostim Vs Eltrobopag

34. Other helpful platelet indices
Platelet indices
MPV PDW
P-LCR IPF
By automated hematology analyzers
Large platelet

35. Romy Approved by
DCGI in HS-ARS
Romiplostim Approved
by US-FDA in HS-ARS